A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA

Daigo Inoyama, Divya Awasthi, Glenn C. Capodagli, Kholiswa Tsotetsi, Paridhi Sukheja, Matthew Zimmerman, Shao Gang Li, Ravindra Jadhav, Riccardo Russo, Xin Wang, Courtney Grady, Todd Richmann, Riju Shrestha, Liping Li, Yong Mo Ahn, Hsin Pin Ho Liang, Marizel Mina, Steven Park, David S. Perlin, Nancy ConnellVéronique Dartois, David Alland, Matthew B. Neiditch, Pradeep Kumar, Joel S. Freundlich

Research output: Contribution to journalArticle

Abstract

Published Mycobacterium tuberculosis β-ketoacyl-ACP synthase KasA inhibitors lack sufficient potency and/or pharmacokinetic properties. A structure-based approach was used to optimize existing KasA inhibitor DG167. This afforded indazole JSF-3285 with a 30-fold increase in mouse plasma exposure. Biochemical, genetic, and X-ray studies confirmed JSF-3285 targets KasA. JSF-3285 offers substantial activity in an acute mouse model of infection and in the corresponding chronic infection model, with efficacious reductions in colony-forming units at doses as low as 5 mg/kg once daily orally and improvement of the efficacy of front-line drugs isoniazid or rifampicin. JSF-3285 is a promising preclinical candidate for tuberculosis. Inoyama et al. disclose the optimization of an indazole antitubercular targeting the β-ketoacyl-ACP synthase KasA. A structure-based approach has overcome significant issues with mouse metabolic stability and pharmacokinetics. A preclinical drug candidate has been delivered with efficacy in a mouse model of chronic M. tuberculosis infection at 5 mg/kg dosing.

Original languageEnglish (US)
Pages (from-to)560-570.e10
JournalCell Chemical Biology
Volume27
Issue number5
DOIs
StatePublished - May 21 2020

Keywords

  • JSF-3285
  • KasA
  • Mycobacterium tuberculosis
  • antitubercular
  • pharmacokinetics
  • structure-based design

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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  • Cite this

    Inoyama, D., Awasthi, D., Capodagli, G. C., Tsotetsi, K., Sukheja, P., Zimmerman, M., Li, S. G., Jadhav, R., Russo, R., Wang, X., Grady, C., Richmann, T., Shrestha, R., Li, L., Ahn, Y. M., Ho Liang, H. P., Mina, M., Park, S., Perlin, D. S., ... Freundlich, J. S. (2020). A Preclinical Candidate Targeting Mycobacterium tuberculosis KasA. Cell Chemical Biology, 27(5), 560-570.e10. https://doi.org/10.1016/j.chembiol.2020.02.007